The amount of bone made by osteoblastic cells and the amount of bone removed or resorbed by osteoclastic cells are balanced in healthy individuals, an imbalance therebetween causing a bone disorder such as bone fracture due to the bone loss, which occurs, e.g., at a rate of over 5% per year in the vertebrae of postmenopausal women. Such symptom can to be attributable to estrogen deficiency, but the mechanism as to how the estrogen deficiency causes bone resorption still remains unresolved.
In order to treat osteoporosis, there is a need to: (a) reduce the rate of bone resorption; (b) raise the rate of bone formation; or (c) perform both (a) and (b). There have been conducted a number of studies on the effects on bone resorption of estrogen, integrin αvβ3 antagonists, cathepsin K inhibitors, and OPG/RANKL/RANK system inhibitors, while studies of the bone formation have also been carried out to examine the effects of novel parathyroid hormone products, calcium sensing receptor antagonists to control the secretion of parathyroid hormone, selective androgen receptor modulators (SARMs), growth hormone secretagogues, insulin-like growth factors, proteosome inhibitors, and TGF-β.
The administration of estrogen, bisphosphonates, calcitonin, or raloxifene has been known to be effective in delaying the bone loss. However, the administration of such a compound over a long period of time induces side effects, e.g., the death or disfunction of osteoclastic cells (Hughes et al., Nat. Med. 2:1132-1136, 1996; Jilka et al., Exp. Hematol. 23:500-506, 1995). Bisphosphonates, in particular, reduce the activity of osteoclastic cells, ultimately leading to cell death (Parfitt et al., J. Bone Miner Res. 11:150-159, 1996; Suzuki et al., Endocrinology 137:4685-4690, 1996).
Currently available therapeutic agents for osteoporosis include bisphosphonates, hormonal drugs, vitamin D, calcitonin, and calcium.
Representative bisphosphonates are alendronate (Merck and Co., Ltd.), risedronate (Hoffman-La Roche Ltd.), zoledronate (Novartis AG; EP Patent No. 275,821), ibandronate (Hoffman-La Roche Ltd.; U.S. Pat. No. 4,942,157), and minodronate (Yamanouchi Pharmaceutical Co., Ltd.; EP Patent No. 354,806), some of which are sold on the market while others are at the clinical trial stages. However, each of them exhibits a low absorption rate of 10% or less through the gastrointestinal tracts, must be administered with a large amount of water before meal, and may cause esophagitis after administration, or osteonecrosis when administered over a long period of time.
Examples of hormonal drugs are raloxifene (Eli Lilly and Co.), droloxyfene (Pfizer Inc.; EP Patent No. 54,168), lasopoxifene (Pfizer Inc., WO 97/16434), FC-1271 (homosmedical Co. and Orion Corp., WO 96/07402), TES-424 (Ligand Co. and Weyers Co., U.S. Pat. No. 5,948,775), but may induce breast and uterine cancers, and accordingly, they are used only limitedly.
Further, vitamin D is expensive and its therapeutic efficacy is not clearly established. Calcitonin is also expensive and requires a difficult method of administration, while calcium, although known to cause little side effects, is effective only for the prevention of osteoporosis and has no therapeutic effect.
It has been found that Runx domain transcription factor (Runx2) is intimately involved in the bone differentiation. Runx2 is an important transcription factor which regulates the expression of early marker alkaline phosphatase (ALP) and late marker osteocalcin (OC) (Ducy, P. et al., Cell 89:747-754, 1997; Mundlos, S. et al., Cell 89:773-779, 1997; Komori, T. et al., Cell 89:755-764, 1997; Otto, F. et al., Cell 89:765-771, 1997). The expression of Runx2 is regulated by Smads, which are signal transmitters activated by BMP (Lee, K. S., et al., Mol. Cell. Biol. 20:8783-8792, 2000). It has also been reported that smurf1 (Smad ubiquitin regulatory factor 1) is a causing factor of ubiquitin-mediated Runx2 protein degradation, and over-expression smurf1 in osteoblast precursor cells leads to the suppression of signal transduction and osteoblast differentiation by the action of BMP (Zhao, M. et al., J. Biol. Chem. 279:12854-12859, 2004; Zhao, M. et al., J. Biol. Chem. 278:27939-27944, 2003). In addition, it has been known that the deacylation and ubiquitination of Runx2 result in the degradation of Runx2 by proteosome, but the treatment with histon deacetylase (HDAC) inhibitor raises the transcription activity of Runx2 to enhance the bone formation (Korean Patent Publication No. 2007-0118986).
The biological usefulness of an amide compound for facilitating bone formation and inhibiting bone loss has not yet been reported. The present inventors have unexpectedly found that bone formation is enhanced and bone loss is inhibited when treated with a specific amide compound.